Method of preparing 7-halogen sterol esters



Patented Feb. 19, 1952 METHOD OF PREPARING 7-HALOGEN STEROL ESTERS JanAnne Keverling Buisma-n, Eindhoven, Netherlands, assignor to HartfordNational Bank and Trust Company, Hartford, Conn, trustee N Drawing.Application July 16, 1947, Serial No. 761,413. In the Netherlands July10, 1946 2 Claims. 1

As is well-known, 7-dehydrosterols, more particularly'7-dehydrocholesterol, may be prepared by esterifying a7-hydroxysterol-3-monoderivative followed by thermal decomposition ofthe ester.

According to the invention, a '7-hydroxysterol- 3-monoester isconverted, by the action of a suitable halogen compound, into a7-halogensterolester from which, as is known in itself, hydrohalogen canbe split off.

Bromine is preferably utilised as the halogen whilst the invention andalso the first-mentioned method are particularly important for thepreparation of 7-bromocholesterol esters, 7-dehydrocholesterolesters andeventually '7-dehydrocholesterol apt to be converted into vitamin-D byirradiation with ultra-violet light.

For converting 7-hydroxysterolester into '7- bromosterolester use ismade, according to one particular mode of realisation, of phosphorustribromide which has been found to be very suitable for this purpose.

According to the invention, it is possible to prepare7-ahalogenstero1esters or 'T-B-halogensterolesters.

Example 0.68 gr. of 7a-hydroxycholesterol-3-benzoate is introduced,together with 2cm. of pyridine and 20 cm. of absolute ether, into aflask provided with a dropping funnel and a calcium chloride tube. Inthe course of a few minutes 1.14 grs. of phosphorus tribromide dissolvedin 5 cm. of absolute ether are added. A white deposit is formed in theflask and only little heat is developed. After letting it stand for onenight ether and water are added, owing to which the larger proportion ofthe deposit dissolves; there remains a gelatinous intermediate layerwhich is neglected. The water layer is once more shaken out with ether,the ether layers being subsequently together shaken out with water.After drying the ether layer is distilled in vacuo. After the residuehas been dried in vacuo above sulphuric acid for the purpose of removingthe pyridine the colourless residue has a weight of 0.59 gr. After theproduct has been recrystalliesed a few times from acetone, we obtain 0.1gr. of pure '7-a-bromocholesterol-benzoate, colourless needles meltingat 138-139 C., decomposing at 140 C. and containing the correct contentsof bromine.

Heating for minutes in an atmosphere of nitrogen in the presence ofdimethylaniline causes conversion into 'T-dehydrocholesterol benzoate.

'7-a-hydroxycholesterol-3benzoate is obtained from7-a-hydroxycholesterol prepared by saponification of7-a-hydroxycholesterol-dibenzoate having a melting point of 171-172 C.(prepared according to Windaus c. s., Annalen der Chemie, 520 98, 1935).The 7-a-hydroxycholesterol is partially esterified by boiling it for 6hours in a benzene solution together with the same quantity by weight ofbenzoic anhydride. After the benzene has been removed by distillationand after the residue has been crystallized from alcohol We obtain 1.4grs. 7a-hydroXycho1esterol-3-benzoate in colourless needles with amelting poin of 191 -192 C.

Starting from 7-fl-hydroxycholesterol-3-benzoate, melting point -166 C.,we obtain 7- ,8-bromooholesterol-3-benzoate in colourless crystals witha melting point of 132-133" C. above which decomposition occurs.

Other 7-halogenstero1esters may also be prepared in similar ways.

What I claim is:

l. The process of preparing 7-bromosterolesters comprising the step ofsubjecting a '7-B-hydroxycholesterol-3-monoester to the action ofphosphorus tribromide without bromine addition at the 3-position, andthereby converting the 7-;3hydroXycho1estero1-3-monoester to thecorresponding 7-13-bromosterolester.

2. The process of preparing a '7-bromosterolester comprising the step ofsubjecting V-e-hydroxycholesterol-S-benzoate to the action of phosphorustribromide without bromine addition at the 3-position, and therebyconverting the 7 b hydroxycholesterol 3 benzoate to 7 bromosterolbenzoate.

JAN ANNE KEVERLING BUISMAN.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 2,098,984 Windaus Nov. 16, 193'?2,215,727 Rosenberg Sept. 24, 194.0 2,395,232 Meuly Feb. 19, 1946FOREIGN PATENTS Number Country Date 574,432 Great Britain Jan. 4, 1946OTHER REFERENCES Ma ker: Jcur. Am. Chem. Soc, vol. 53, pp. 481-482(1936).

Wintersteiner et al.: Jour. Am. Chem. Soc. .65, 1503-1507 (1943).

1. THE PROCESS OF PREPARING 7-BROMOSTEROLESTERS COMPRISING THE STEP OFSUBJECTING A 7-B-HYDROXYCHOLESTEROL-3-MONOESTER TO THE ACTION OFPHOSPHOROUS TRIBROMIDE WITHOUT BROMINE ADDITION AT THE 3-POSITION, ANDTHEREBY CONVERTING THE 7-B-HYDROXYCHOLESTEROL-3-MONOESTER TO THECORRESPONDING 7-B-BROMOSTEROLESTER.